Publication: Efecto de la elevación precoz de progesterona sobre la efectividad de la fecundación in vitro
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2017-02-15
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Universidad Complutense de Madrid
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Abstract
La elevación precoz de progesterona ha sido catalogada como un efecto colateral desfavorable de la estimulación ovárica, que produce un aumento de la masa de células granulosas capaces de sintetizar progesterona y favorece su producción. La exposición precoz del endometrio a la progesterona puede producir una alteración de la regulación de la ventana de implantación, y reducir la probabilidad de implantación embrionaria, de gestación clínica y de nacido vivo. El efecto de la progesterona puede ser interferido por el de otras variables que pueden condicionar el resultado gestacional del ciclo de FIV-TE. En concreto, se ha sugerido que la intensidad de respuesta a la estimulación y la dosis de gonadotropinas pueden estar en relación con la cantidad de progesterona sintetizada. Igualmente, el número de ovocitos obtenidos y el número y calidad de los embriones disponibles y transferidos podrían modular el efecto adverso de la elevación precoz de progesterona. OBJETIVOS: Evaluar la asociación de la elevación precoz de progesterona con la frecuencia de nacido vivo, ajustando su efecto por el resto de variables independientes relacionadas con este resultado. Como objetivo secundario, el estudio pretende analizar la asociación con implantación embrionaria, gestación clínica y aborto, METODOLOGÍA: Análisis de asociación entre exposición a elevación precoz de progesterona y variables de resultado gestacional, mediante pruebas estadísticas de contraste adecuadas. Estimación de magnitud de efecto, mediante el riesgo relativo y la diferencia de riesgos, aplicando análisis univariado, bivariado y multivariado RESULTADOS: Se analiza una cohorte de 3741 ciclos de FIV con transferencia embrionaria, realizados entre 2003 y 2013. Se ha identificado asociación significativa entre la progesterona sérica en el día de la HCG y la frecuencia de implantación embrionaria, gestación clínica y nacido vivo, pero no con aborto. Se ha estimado un umbral de exposición a progesterona para cada tipo de resultado. Ninguna de las covariables asociadas tanto con obtención de nacido vivo como con la elevación precoz de la progesterona ejerció interacción ni confusión en el efecto de la progesterona sobre el resultado del ciclo. La elevación de la progesterona sérica, junto con la dosis de FSH, el número de embriones transferidos y de calidad, y la existencia de embriones para criopreservar se asociaron como a la obtención de nacido vivo variable independiente. El número de ovocitos obtenidos y el tratamiento con LH no fueron identificadas como variables independientes. CONCLUSIONES: La elevación precoz de progesterona reduce la frecuencia de nacido vivo, y se asocia a menor frecuencia de implantación y gestación clínica, pero no muestra relación con aborto. El punto de corte en la distribución de progesterona más adecuado para estimar el efecto fue distinto para cada resultado. La asociación entre elevación precoz de progesterona y reducción de al frecuencia de nacido vivo no fue interferida por el efecto de ninguna covariable. La elevación precoz de progesterona tuvo un efecto sobre la frecuencia de nacido vivo independiente del resto de las variables explicativas (edad, dosis de FSH, número y calidad de los embriones disponibles y transferidos, y existencia de embriones para criopreservar)...
Progesterone elevations were first described, during follicular advanced stages of ovarian stimulation in IVF treatments, occurred in the context of cycles without suppression of pituitary function by using GnRH analogues. These elevations were blamed on the occurrence of undetected peaks of endogenous LH in response to supraphysiological increase of estradiol. In the cycles with multiple follicular development, the absence of a dominant follicle dominance and multiple development of greater follicles cohort, leads to supraphysiological estradiol synthesis and an increase in progesterone production. This phenomenon is known as premature luteinization. However the systematic use of GnRH analogues has not suppressed the progesterone early elevations in all cases. "Premature luteinization" has lost relevance today, since in most PPE, can not show increases in serum LH. EEP deleterious effect on pregnancy in IVF cycles remains controversial. The early increase in progesterone (PPE) has been described with frequencies ranging 35-38% of stimulation cycles under protocol agonist or antagonist to far lower of 8.9% estimated large retrospective studies . Most frequently used indicator to estimate EPP incidence is serum on the day of hCG administration, which can be a source of systematic error. Heterogeneity of these observations are probably due to different causes. Most PPE initial studies defined by arbitrary stratifications in serum progesterone level in ranges of between 0.8 and 2 ng / mL. Most recently published studies, also made with modern methods of quantification have selected more consistently cut of levels of 1.5 ng / mL of serum progesterone rise. OBJECTIVES To asses early progesterone association with life birth rate, adjusting by independents related variables. As a secondary goal we aim to asses association with implantation, pregnancy and miscarriage rate. METHODS Association analysis between early progesterone rise and primary results variables, on going pregnancy . Estimation o effects magnitude thru relative risk, difference of risks, with contrast appropriate statistical tests. We have applied univariate, bivariate and multivariate analysis. RESULTS We analyse 3741 cycles of transferred IVF patients with known pregnancy results between 2003 and 2013. We have identified a significative correlation between serum progesterone on HCG, and implantation rate, on going pregnancy rate and life birth rate but not with miscarriage. We have estimated the cut of value for all the associated results variables. CONCLUSIONS Early progesterone elevation reduces life birth rates, on on going pregnancy rates and implantation rates but it does not affect miscarriage. The cut of point in our sample was different for each of the results variables. Association between early progesterone elevation and life birth rate was not affected for any of the other potential modifying factors. Early progesterone rise had an independent effect on life birth rate which was not affected by any other modifying variables (age, FSH dosages, number and quality of embryos available and transferred and cryopreserved embryos)...
Progesterone elevations were first described, during follicular advanced stages of ovarian stimulation in IVF treatments, occurred in the context of cycles without suppression of pituitary function by using GnRH analogues. These elevations were blamed on the occurrence of undetected peaks of endogenous LH in response to supraphysiological increase of estradiol. In the cycles with multiple follicular development, the absence of a dominant follicle dominance and multiple development of greater follicles cohort, leads to supraphysiological estradiol synthesis and an increase in progesterone production. This phenomenon is known as premature luteinization. However the systematic use of GnRH analogues has not suppressed the progesterone early elevations in all cases. "Premature luteinization" has lost relevance today, since in most PPE, can not show increases in serum LH. EEP deleterious effect on pregnancy in IVF cycles remains controversial. The early increase in progesterone (PPE) has been described with frequencies ranging 35-38% of stimulation cycles under protocol agonist or antagonist to far lower of 8.9% estimated large retrospective studies . Most frequently used indicator to estimate EPP incidence is serum on the day of hCG administration, which can be a source of systematic error. Heterogeneity of these observations are probably due to different causes. Most PPE initial studies defined by arbitrary stratifications in serum progesterone level in ranges of between 0.8 and 2 ng / mL. Most recently published studies, also made with modern methods of quantification have selected more consistently cut of levels of 1.5 ng / mL of serum progesterone rise. OBJECTIVES To asses early progesterone association with life birth rate, adjusting by independents related variables. As a secondary goal we aim to asses association with implantation, pregnancy and miscarriage rate. METHODS Association analysis between early progesterone rise and primary results variables, on going pregnancy . Estimation o effects magnitude thru relative risk, difference of risks, with contrast appropriate statistical tests. We have applied univariate, bivariate and multivariate analysis. RESULTS We analyse 3741 cycles of transferred IVF patients with known pregnancy results between 2003 and 2013. We have identified a significative correlation between serum progesterone on HCG, and implantation rate, on going pregnancy rate and life birth rate but not with miscarriage. We have estimated the cut of value for all the associated results variables. CONCLUSIONS Early progesterone elevation reduces life birth rates, on on going pregnancy rates and implantation rates but it does not affect miscarriage. The cut of point in our sample was different for each of the results variables. Association between early progesterone elevation and life birth rate was not affected for any of the other potential modifying factors. Early progesterone rise had an independent effect on life birth rate which was not affected by any other modifying variables (age, FSH dosages, number and quality of embryos available and transferred and cryopreserved embryos)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Obstetricia y Ginecología, leída el 03-02-2016